The invention generally relates to methods and formulations for treating infectious bursal disease in avian subjects.
Infectious bursal disease virus (xe2x80x9cIBDVxe2x80x9d) causes a highly contagious immunosuppressive disease in avian species (e.g., chickens and turkeys). See Luckert, P. D. et al., Avian Dis. 18, 243-251 (1974). The disease is believed to severely deplete the bursa of Fabricius and/or the spleen of the B-cells and other immunoprotective cells necessary for mounting an antibody response to infectious agents. If infectious bursal disease (IBD) does not directly result in death, the resulting immunosuppression can leave the bird susceptible to other infections and reduce its ability to respond to vaccination. Thus, the disease poses a significant problem to the poultry industry.
Vaccination efforts are intended to prevent serious losses from xe2x80x9cclinicalxe2x80x9d IBD in which mortality may exceed five percent and morbidity 100 percent. For example, breeding hens are typically vaccinated with a combination of live virus (e.g., at four to six weeks of age) and inactivated virus (e.g., at 18 to 20 weeks of age). The hens are typically monitored serologically for IBDV antibody to ensure protection for themselves, and to maintain adequate maternal IBDV antibody levels in the chicks. Maternal antibody may provide protection for several days (e.g., three to seven days) or, if oil emulsion type vaccines are employed, four to five weeks. The level of protection has been reported to vary from chick to chick. See Baxendale, W. et al., Dev. Biol. Stand. 51, 211-219 (1981) and Lucio, B. et al., Avian Dis. 23, 466-478 (1979). Some commercial operations also vaccinate day old chicks in ovo, and later with additional field boosts (typically one or more). The timing of the vaccination is believed to be important. The proper time to vaccinate typically varies depending upon maternal antibody level, route of vaccination, and virulence of the vaccine virus.
In recent years, xe2x80x9csubclinicalxe2x80x9d IBDV infection, associated with variant vaccine strains, have become more common. The disease typically appears less severe and the inflammatory response in the bursa usually is less pronounced than with full-blown IBDV infection. Nonetheless, immunosuppression may still occur. Infection and immunosuppression continue to be common despite the substantial investment by poultry producers in the vaccines, serological monitoring, and labor involved in vaccination administration. Accordingly, there is a need in the art for more effective methods of treating and preventing IBD than are currently practiced.
In one aspect, the invention relates to a method of treating infectious bursal disease (IBD) in an avian subject in need of such treatment. The method comprises administering to the subject a compound selected from the group consisting of formulas (I) through (IV): 
and the pharmaceutically acceptable salts thereof, wherein:
p is an integer ranging from one to eight;
A is selected from O, S, and NR, wherein R may be H or loweralkyl;
Xxe2x80x2, Xxe2x80x3, X3, X4, X5, X6, R1, R2, R3, and R4 are independently selected and each represented by loweralkyl, loweralkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, alkylaryl, halogen or: 
wherein:
each R22 and R23 is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, and alkylaryl, or two R22 groups together represent C2-C10 alkyl, hydroxyalkyl, or alkylene, or the two R22 groups together represent cycloalkyl, or: 
wherein r is from one to three and R13 is H, 
or xe2x80x94CONHR10NR11R12, wherein:
R10 is loweralkyl; R11 and R12 are independently selected from the group consisting of H and lower alkyl; each R8 is independently selected from the group consisting of H, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, and alkylaryl, or two R8 groups together represent C2-C10 alkylene; R9 is H, hydroxy, loweralkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl, aryl, or alkylaryl; wherein Xxe2x80x2 and Xxe2x80x3 may be in the meta or para positions;
X1 and X2 are independently selected from the group consisting of H, loweralkyl, and loweralkoxy;
and wherein the compound represented by formulas (I), (II), (III), or (IV) is administered in an amount to treat the IBDV.
In one embodiment, the compound is represented by the formula: 
wherein p, R1, and R2 are as previously defined. In this embodiment, the compound is preferably represented by the formula: 
In another embodiment, the compound is represented by the formula: 
wherein Xxe2x80x2, Xxe2x80x3, and A are as previously defined. In this embodiment, the compound is preferably represented by the formula: 
In another embodiment, the compound is represented by the formula: 
In yet another embodiment, the compound is represented by the formula: 
wherein X1, X2, X3, and X4 are as previously defined. In this embodiment, the compound may be of the formula: 
The compound in this embodiment may also be of the formula: 
In still another embodiment, the compound is represented by the formula: 
wherein X5 and X6 are as defined above. A preferred compound in this embodiment is represented by the formula: 
In another aspect, the invention provides a method for producing active immunity against infectious bursal virus disease (IBDV) in an avian subject. The method comprises administering to a subject an immunogenic-amount of an IBDV vaccine and a compound selected from the group consisting of formulas (I) through (IV) or a pharmaceutically acceptable salt thereof.
Another aspect of the invention relates to a pharmaceutical formulation for the treatment of IBD, comprising a compound of the present invention as set forth above in a pharmaceutically acceptable carrier.